Ethinylestradiol
Synthetic estrogen in hormonal contraceptives
Ethinylestradiol is a synthetic estrogen known since the late 1930s and, since the 1960s, a central component of most combined hormonal contraceptives. Chemical modification at the C17 carbon atom (introduction of an ethinyl group) makes the substance orally active because it survives hepatic first pass metabolism better than natural estradiol. Ethinylestradiol is used in combination products with progestins such as levonorgestrel, desogestrel, drospirenone, dienogest or chlormadinone acetate.
Numerous combination products containing ethinylestradiol are available in Germany, from classics such as Microgynon and Valette to modern preparations with 20 or 30 µg ethinylestradiol per tablet. The dose has been markedly reduced over the decades in order to lower side effects and thromboembolic risks. Modern oral contraception almost exclusively uses doses between 15 and 35 µg; higher dosed preparations are reserved for rare indications such as acne, hyperandrogenism or bleeding disorders.
Mechanism of Action
Ethinylestradiol binds with high affinity to estrogen receptors α and β, activates transcription of estrogen dependent genes and modulates the hypothalamic pituitary axis. In combination with a progestin, daily intake suppresses pulsatile GnRH release and consequently LH and FSH secretion. Follicular maturation fails to occur and the ovulation point is not reached. The progestin component additionally thickens cervical mucus and reduces endometrial receptivity.
The contraceptive principle is therefore threefold: inhibition of ovulation, alteration of cervical mucus and endometrial transformation with reduced implantation capacity. The contraceptive reliability of combined oral contraceptives containing ethinylestradiol shows a Pearl Index below 0.5 with correct use, but in real practice with occasional missed pills it ranges from 5 to 9.
Beyond contraception, ethinylestradiol influences numerous hepatic proteins. It increases the synthesis of clotting factors, angiotensinogen, SHBG, transferrin, thyroxine binding globulin and cortisol binding globulin. These changes explain both the increased thromboembolic tendency and effects on blood pressure and thyroid values. At the same time, ethinylestradiol lowers free testosterone through a rise in SHBG, which enables its use for acne and hirsutism.
Indications
- Combined hormonal contraception in women of childbearing age without risk factors
- Cycle regulation in polymenorrhea, dysmenorrhea, hypermenorrhea
- Acne and hirsutism with hyperandrogenism in combination with antiandrogenic progestins
- Functional ovarian cysts to prevent recurrence
- Endometriosis to relieve cycle dependent symptoms
- Menstrual cycle shifting in exceptional situations with regular intake
For pure hormone replacement therapy in menopause, ethinylestradiol is not used because of its less favourable hepatic profile; bioidentical estradiol or conjugated estrogens are preferred instead.
Dosage and Administration
Combination preparations: depending on formulation, 15, 20, 30 or 35 µg ethinylestradiol daily over 21 to 28 days. Intake occurs daily at the same time, mostly in the evening, to minimise nausea. In 28 day packs the last 4 to 7 tablets are placebo; in 21 day packs a seven day break follows.
The cycle starts on the first day of menstruation or, after consultation, on the first Sunday. When switching from another hormonal preparation, the new product should be started seamlessly. After a termination of pregnancy or delivery without breastfeeding, intake usually starts between day 21 and 28.
Missed tablet: if less than 12 hours have passed, take the tablet immediately and continue as usual. If more than 12 hours have passed, contraceptive reliability may be impaired; depending on the week of intake add 7 days of barrier contraception and, if necessary, continue through to the next break. Exact handling follows the protocol of the respective package leaflet.
Hepatic impairment: contraindicated in severe impairment. Renal impairment: no formal adjustment, but caution in hypertension associated nephropathy. Older patients and smokers over 35 years: combined pills are contraindicated because of markedly increased cardiovascular risk; prefer alternative methods.
Side Effects
Very common and common: breakthrough bleeding especially in the first months, nausea, headache, breast tenderness, weight changes, mood swings, decreased libido, acne or improvement of acne depending on the progestin partner, fluid retention, vaginal discharge.
Uncommon: migraine, depression, dizziness, blood pressure rise, galactorrhea, chloasma, liver tumours (rare but reported), gallbladder disorders, contact lens intolerance.
Rare to very rare but serious: venous thromboembolism (deep vein thrombosis, pulmonary embolism), arterial thromboembolism (myocardial infarction, stroke), hypertension, liver tumours, hepatitis, worsening of migraine with aura, visual disturbances.
Thromboembolic risk: risk is highest in the first year of use, with obesity, smoking, thrombophilia (Factor V Leiden, prothrombin mutation), prolonged immobilisation and with third or fourth generation progestins (desogestrel, gestodene, drospirenone). Preparations with levonorgestrel or norethisterone carry the lowest thromboembolic risk.
Interactions
- Enzyme inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort, efavirenz, nevirapine): marked reduction in ethinylestradiol plasma levels, contraceptive reliability compromised, use alternatives
- HIV protease inhibitors and non nucleoside reverse transcriptase inhibitors: variable effects, individual clarification needed
- Antibiotics (amoxicillin, tetracyclines, macrolides): clinically usually not relevant; with diarrhoea or vomiting add a barrier method. Rifampicin and rifabutin are the notable exceptions
- Anticoagulants: warfarin effect may be altered, monitor INR
- Antihypertensives: ethinylestradiol may raise blood pressure, adjust antihypertensive therapy if needed
- Lamotrigine: ethinylestradiol lowers lamotrigine levels, seizure breakthrough possible
- Thyroid hormones: increased TBG binding, under substitution therapy monitor TSH and adjust dose
Special Notes
Contraindications: past or current venous or arterial thromboembolism, cerebrovascular disease, migraine with aura, untreated hypertension, diabetes with vascular damage, hormone dependent malignancies, severe hepatic dysfunction, liver tumours, undiagnosed genital bleeding, known pregnancy, smoking in women over 35, severe obesity (BMI above 35), thrombophilia.
Counselling and disclosure: before first prescription conduct a detailed history focused on thromboembolic risk factors, blood pressure, smoking, BMI. Annual review at the medical practice with blood pressure measurement is standard. Document and discuss the risks and warning signs of thrombosis (unilateral leg pain, swelling, shortness of breath, chest pain).
Pregnancy: contraindicated; on confirmed pregnancy discontinue immediately. Contrary to older assumptions, there is no evidence of teratogenicity with inadvertent intake in early pregnancy. Lactation: ethinylestradiol may reduce milk production; the progestin only pill or other non hormonal methods are preferable during the first 6 months post partum.
Surgery and immobilisation: for planned major surgery or prolonged immobilisation, stop the combined pill 4 to 6 weeks beforehand and switch to an alternative in order to minimise thrombosis risk. Therapy may be resumed about 2 weeks after mobilisation.
Monitoring: blood pressure every six to twelve months, more often with risk factors. Laboratory investigations such as liver values, lipids, glucose depending on history. Mammography and cancer screening according to age appropriate programmes.
You Might Also Be Interested In
- Dienogest, progestin in modern contraceptives and for endometriosis
- Leuprorelin, GnRH analogue in endometriosis and hormone dependent tumours
- Letrozole, aromatase inhibitor in breast cancer
- Relugolix, oral GnRH antagonist in endometriosis and prostate cancer
- Fezolinetant, non hormonal therapy of menopausal symptoms
Frequently Asked Questions
What is my thrombosis risk on the pill?
Absolute risk of venous thromboembolism in women without risk factors is approximately 5 to 12 per 10000 users per year, depending on the progestin partner. By comparison, the baseline risk without the pill is 2 per 10000 per year, in pregnancy 30, and in the postpartum period 70 per 10000 per year. Smoking, obesity and thrombophilia raise the risk further.
Will I gain weight on the pill?
Modern preparations with low ethinylestradiol doses rarely lead to relevant weight gain. Some women report mild fluid retention that is reversible. A gain of more than 3 kg in the first year without lifestyle changes deserves a review. Switching to a preparation with a different progestin partner may help.
Can I take the pill with migraine?
In migraine without aura, use is possible under strict risk assessment. In migraine with aura, the combined pill is contraindicated because of a markedly increased risk of ischaemic stroke. Alternatives include the progestin only pill, progestin implants, hormonal intrauterine systems or non hormonal contraception.
Do antibiotics make the pill less effective?
Clinically relevant interaction occurs practically only with rifampicin and rifabutin. Other antibiotics do not meaningfully impair contraceptive reliability according to current evidence. During vomiting or diarrhoea under antibiotic therapy, absorption may be impaired; then adding a barrier method for 7 days is sensible.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline Hormonal Contraception
- Gelbe Liste, Ethinylestradiol active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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